High chronic caffeine consumption by humans can lead to a syndrome known as caffeinism, a common manifestation of which is anxiety. Since this anxiety is often indistinguishable from anxiety neurosis, the present proposal suggests that caffeine administration to animals may eventually provide a pharmacological model of anxiety. Caffeine and other methylxanthines have recently been shown to block brain adenosine receptors in vitro. Since adenosine generally produces an inhibition of CNS neuron firing, caffeine, through adenosine blockade, might decrease this inhibition thus leading to an anxiety state. The present studies will utilize locomotor activity as a behavioral measure since the potency of caffeine and other methylxanthines to block adenosine receptors in vitro correlates with their potency in increasing locomotor activity. If caffeine acts as an antagonist at adenosine receptors, then chronic caffeine administration might be expected to increase the number of adenosine receptors because of compensatory changes in the CNS. If this increase is functionally significant, then the locomotor response to drugs acting at adenosine receptors should be modified accordingly. Inbred strains of mice will be used in these studies as a model system for the possible genetic basis of individual variability in response to caffeine in humans. Thus, the present proposal will, first of all, determine if there are differences in the locomotor response to acute administration of caffeine and an adenosine agonist among three inbred strains of mice. If behavioral differences are seen, studies will assess whether they are related to differences in brain adenosine receptor binding among the strains. Then the effects of chronic caffeine administration on the locomotor response to caffeine itself (to evaluate tolerance) and to the adenosine agonist (to evaluate supersensitivity) and also on adenosine receptor binding will be determined. These studies will therefore provide the groundwork for a pharmacological model of anxiety involving the interaction of caffeine with adenosine receptors which could be expanded in the future to include other behaviors, interactions with anxiolytics such as benzodiazepines and other drugs taken with caffeine such as alcohol and nicotine, and developmental aspects of adenosine receptors and the behavioral response to caffeine.